Data_Sheet_2_Growth Differentiation Factor 15 Predicts Cancer Death in Patients With Cardiovascular Risk Factors: The J-HOP Study.pdf

Background: Disease-related anorexia-cachexia is associated with poor prognosis of patients with cardiovascular disease (CVD) or cancer. Growth differentiation factor-15 (GDF-15) has emerged as a central regulator of appetite and body weight. However, the exact role of GDF-15 in lean patients has not been elucidated.
Aim: Our aim is to evaluate whether the association of GDF-15 with mortality, including cancer death, differs according to body mass index (BMI) level.
Methods and Results: We collected blood samples from 4,061 patients with CV risk factors who were enrolled in the nationwide practice-based J-HOP (Japan Morning Surge-Home Blood Pressure) study. Serum GDF-15 levels were determined by immunoassay analysis. During a mean follow-up period of 6.6 years, we observed 174 (6.7/1000 person-year) all-cause deaths, 68 (2.6/1000 person-year) cancer deaths, and 56 (2.2/1000 person-year) CV deaths. Patients were stratified according to the cut-points of GDF-15 at 1,200 ng/L and BMI at 22.5 and 25.0 kg/m2. The association between the GDF-15/BMI based study groups and each outcome was evaluated by Cox-proportional hazard models with adjustment for established risk factors. The multivariate Cox regression model showed that patients with elevated GDF-15 (≥1,200 ng/L) and low BMI (<22.5 kg/m2) were significantly associated with increased risk of all outcomes [all-cause death, hazard ratio (HR) 3.15, 95% confidence interval (CI) 1.85–5.34, p < 0.001; cancer death, HR 3.52, 95%CI 1.64–7.57, p = 0.001; CV death, HR 2.88, 95%CI 1.20–6.92, p = 0.018, respectively] compared to a reference group with non-elevated GDF-15 and normal BMI (22.5–25.0 kg/m2). In analyses of a subgroup with low BMI (<22.5 kg/m2), patients with elevated GDF-15 had 4.79-fold increased risk of cancer death and 11-fold greater risk of CV death when compared with patients with non-elevated GDF-15 (<1,200 ng/L) after adjustment for established risk factors.
Conclusion: In patients with CV risk factors, GDF-15 was associated with all-cause, cancer, and CV death. This relationship was especially remarkable in patients with low BMI. The serum GDF-15 levels in patients with low BMI might be a useful marker to identify the potential for anorexia-cachexia associated with CVD and cancer.

背景：疾病相关厌食-恶病质（disease-related anorexia-cachexia）与心血管疾病（cardiovascular disease, CVD）或癌症患者的不良预后密切相关。生长分化因子-15（growth differentiation factor-15, GDF-15）现已被确认为食欲与体重的核心调节因子，但目前其在体瘦患者中的确切作用仍未阐明。
研究目的：本研究旨在探讨GDF-15与包括癌症死亡在内的全因死亡率之间的关联是否会因体质量指数（body mass index, BMI）水平不同而存在差异。
方法与结果：本研究纳入全国性基于临床实践的J-HOP（日本晨间血压波动-家庭血压）研究中的4061名合并心血管危险因素的患者，采集其血液样本，采用免疫分析法测定血清GDF-15水平。在平均6.6年的随访期间，共观察到174例全因死亡（发生率6.7/1000人年）、68例癌症死亡（发生率2.6/1000人年）以及56例心血管死亡（发生率2.2/1000人年）。研究对象以GDF-15 1200ng/L作为截点值，以BMI 22.5、25.0kg/m²作为截点值进行分组。采用校正已确立危险因素的Cox比例风险模型（Cox-proportional hazard model），评估基于GDF-15/BMI的分组与各研究结局之间的关联。多因素Cox回归分析结果显示，与GDF-15正常且BMI处于22.5~25.0kg/m²的参照组相比，GDF-15升高（≥1200ng/L）且BMI偏低（<22.5kg/m²）的患者，其全因死亡、癌症死亡及心血管死亡风险均显著升高[全因死亡：风险比（hazard ratio, HR）3.15，95%置信区间（confidence interval, CI）1.85~5.34，p<0.001；癌症死亡：HR 3.52，95%CI 1.64~7.57，p=0.001；心血管死亡：HR 2.88，95%CI 1.20~6.92，p=0.018]。在BMI偏低（<22.5kg/m²）的亚组分析中，校正已确立的危险因素后，与GDF-15正常（<1200ng/L）的患者相比，GDF-15升高者的癌症死亡风险升高4.79倍，心血管死亡风险升高11倍。
结论：在合并心血管危险因素的患者中，血清GDF-15水平与全因死亡、癌症死亡及心血管死亡均存在显著关联，且该关联在BMI偏低的患者中尤为突出。体瘦患者的血清GDF-15水平或可作为识别心血管疾病及癌症相关厌食-恶病质潜在风险的有效生物标志物。